title: Longitudinal evaluation of left ventricular substrate metabolism, perfusion, and dysfunction in the spontaneously hypertensive rat model of hypertrophy using small-animal PET/CT imaging.
abstract: Myocardial metabolic and perfusion imaging is a vital tool for understanding the physiologic consequences of heart failure. We used PET imaging to examine the longitudinal kinetics of (18)F-FDG and 14(R,S)-(18)F-fluoro-6-thia-heptadecanoic acid ((18)F-FTHA) as analogs of glucose and fatty acid (FA) to quantify metabolic substrate shifts with the spontaneously hypertensive rat (SHR) as a model of left ventricular hypertrophy (LVH) and failure. Myocardial perfusion and left ventricular function were also investigated using a newly developed radiotracer (18)F-fluorodihydrorotenol ((18)F-FDHROL).
  
  
  METHODS
  Longitudinal dynamic electrocardiogram-gated small-animal PET/CT studies were performed with 8 SHR and 8 normotensive Wistar-Kyoto (WKY) rats over their life cycle. We determined the myocardial influx rate constant for (18)F-FDG and (18)F-FTHA (Ki(FDG) and Ki(FTHA), respectively) and the wash-in rate constant for (18)F-FDHROL (K1(FDHROL)). (18)F-FDHROL data were also used to quantify left ventricular ejection fraction (LVEF) and end-diastolic volume (EDV). Blood samples were drawn to independently measure plasma concentrations of glucose, insulin, and free fatty acids (FFAs).
  
  
  RESULTS
  Ki(FDG) and Ki(FTHA) were higher in SHRs than WKY rats (P < 3 × 10(-8) and 0.005, respectively) independent of age. A decrease in Ki(FDG) with age was evident when models were combined (P = 0.034). The SHR exhibited higher K1(FDHROL) (P < 5 × 10(-6)) than the control, with no age-dependent trends in either model (P = 0.058). Glucose plasma concentrations were lower in SHRs than controls (P < 6 × 10(-12)), with an age-dependent rise for WKY rats (P < 2 × 10(-5)). Insulin plasma concentrations were higher in SHRs than controls (P < 3 × 10(-3)), with an age-dependent decrease when models were combined (P = 0.046). FFA levels were similar between models (P = 0.374), but an increase with age was evident only in SHR (P < 7 × 10(-6)).
  
  
  CONCLUSIONS
  The SHR exhibited alterations in myocardial substrate use at 8 mo characterized by increased glucose and FA utilizations. At 20 mo, the SHR had LVH characterized by decreased LVEF and increased EDV, while simultaneously sustaining higher glucose and similar FA utilizations (compared with WKY rats), which indicates maladaptation of energy substrates in the failing heart. Elevated K1(FDHROL) in the SHR may reflect elevated oxygen consumption and decreased capillary density in the hypertrophied heart. From our findings, metabolic changes appear to precede mechanical changes of LVH progression in the SHR model.
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Hernandez
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Huber
authors.forename: Stephanie T
authors.initials: ST
authors.lastname: Murphy
authors.forename: Mustafa
authors.initials: M
authors.lastname: Janabi
authors.forename: Gengsheng L
authors.initials: GL
authors.lastname: Zeng
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Brennan
authors.forename: James P
authors.initials: JP
authors.lastname: O'Neil
authors.forename: Youngho
authors.initials: Y
authors.lastname: Seo
authors.forename: Grant T
authors.initials: GT
authors.lastname: Gullberg
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified / Q000097:blood; D019788:Fluorodeoxyglucose F18; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D008137:Longitudinal Studies; D008297:Male; D064847:Multimodal Imaging; D055414:Myocardial Perfusion Imaging; D010641:Phenotype; D049268:Positron-Emission Tomography; D051381:Rats; D011918:Rats, Inbred SHR; D014057:Tomography, X-Ray Computed
chemical_list: D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D019788:Fluorodeoxyglucose F18; C071178:14-fluoro-6-thiaheptadecanoic acid
keywords: 18F-fluoro-6-thia-heptadecanoic acid; 18F-fluorodihydrorotenol; myocardial perfusion; myocardial substrate metabolism; spontaneously hypertensive rat